CN109384823B - Two piericins glucoside and application thereof in anti-renal cancer drugs - Google Patents
Two piericins glucoside and application thereof in anti-renal cancer drugs Download PDFInfo
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Abstract
The invention discloses two piericins glucoside and application thereof in anti-renal cancer drugs. The invention discloses the inhibitory activity of the piericidin glucoside glucoperidin A and 7-demethylglucoperidin A on three kidney cancer cells for the first time, and the piericidin glucoside can be used for preparing anti-kidney cancer drugs. Therefore, the invention provides an alternative compound for developing a new anti-renal cancer drug and has important significance for developing Chinese marine microbial drug resources.
Description
The technical field is as follows:
the invention belongs to the field of microbial natural products, and particularly relates to two microbial sources of piericidin glucoside and application thereof in preparation of anti-renal cancer drugs.
Background art:
malignant tumors have long been one of the major diseases that seriously jeopardize human life and quality of life. The malignant tumor is reported to become the leading cause of death of residents in China, and the death rate of the malignant tumor in China continuously shows an increasing trend for nearly 20 years and is even in the front of the death rate of the malignant tumor in the world. For the treatment of malignant tumor, natural products and their derivatives play an important role. It is reported that antitumor drugs derived from natural products account for more than 60% of antitumor drugs on the market between 1981 and 2008, and the number of novel natural products and derivatives thereof as new antitumor drugs is increasing. Renal cancer is one of ten major dead cancers in the world, and the incidence rate of the renal cancer is second to bladder cancer in urinary system tumors in China. It has been found that 30% of patients with renal cancer develop metastasis, and another 30% are at risk of developing metastasis within 10 years, and metastatic renal cancer has high resistance to radiotherapy and chemotherapy and systemic treatment.
Piericidins (Piericidins) are α -pyridone antibiotics of microbial origin, and as of 2017, 41 natural Piericidins products, all produced by land and marine actinomycetes, have been found. The piericins are reported to have activities of killing insects, resisting bacteria and the like, and also have inhibitory activity on partial tumor cells, but the research on the action mechanism is very weak, and the anti-tumor potential needs to be further excavated.
The invention content is as follows:
the first object of the present invention is to provide two of the piericidin glucosides glucopteridin A, 7-demethylglucopteridin A, as shown in formula (I), or pharmaceutically acceptable salts thereof.
The structural formula of the leptomycin compound glucopericidin A is shown as a formula (I), wherein R is CH3；
The structural formula of the piericidin compound 7-demethylglucoptericidin A is shown in a formula (I), wherein R is H.
The inventor obtains two pulveromyces farinosus glucoside glucoperidin A and 7-demethylglucoperidin A by performing shaking table amplification fermentation and extraction purification on Streptomyces sp.HBERC-58855 (disclosed in patent application No. 201710344174.3, which is preserved in China type culture collection in 2017, 4 and 10 days, with the preservation address of university in China, Wuhan and Wuhan, the preservation date of the university in 2017, 4 and 10 days, and the preservation number of CCTCC NO: M2017186) from mangrove forest sediment.
The evaluation of the in vitro anti-renal cancer activity of two piericins glucoside shows that glucoptericidin A and 7-demethylglucoptericidin A have weaker cytotoxicity on human renal tubular epithelial cells (normal tissue cells) HK-2 and show lower toxicity; glucopericidin A has selective inhibitory activity on human renal carcinoma cell ACHN cell (half inhibition rate IC)500.21 mu M) is stronger than the positive drug sorafenib and the similar natural product Piericidin A. 7-demethylglucoptericidin A has strong broad-spectrum inhibitory activity (IC) on three renal cancer cells ACHN, OS-RC-2 and 786-O500.31-2.6 mu M), all are stronger than the inhibition activity of sorafenib on corresponding cells. The inhibitory activity on renal cancer ACHN cells is equivalent to that of piericidin A, but the inhibitory activity on renal cancer OS-RC-2 and 786-O is stronger than that of piericidin A. 7-demethylglucoptericidin A can remarkably induce the apoptosis of the ACHN of renal cancer cells under the concentration of 0.2 mu M.
Compared with piericidin A, the two pulverycin glucoside glucoptericidin A and 7-demethylglucoptericidin A mainly increase glucosyl fragments on a chemical structure, not only enhance the anti-renal cancer activity, but also increase the polarity of a compound and improve the oil-water distribution coefficient, thereby having better drug forming property than the piericidin A. Therefore, the compounds can be used as lead compounds for developing anti-renal cancer drugs.
Therefore, the second purpose of the invention is to provide the application of two pulveromycetin glucoside A and/or 7-demethylglucoptericidin A shown in the formula (I) or medicinal salts thereof in preparing anti-renal cancer drugs.
The third purpose of the invention is to provide an anti-renal cancer medicament, which is characterized by comprising effective amount of pulveromycetin glucoside glucopericidin A and/or 7-demethylglucopericidin A shown in formula (I) as active ingredients, or medicinal salt thereof, and pharmaceutically acceptable carrier.
The fourth purpose of the invention is to provide the preparation method of the piericidin A and/or the 7-demethylglucopteridin A, which is prepared and separated from the fermentation culture of Streptomyces sp.HBERC-58855.
Preferably, the specific steps are as follows: extracting fermentation product of Streptomyces sp.HBERC-58855 with ethyl acetate, concentrating the extract to obtain extract, and subjecting the extract to silica gel column chromatography with petroleum ether; petroleum ether: 1:1v/v of dichloromethane; dichloromethane; dichloromethane: methanol 100:1 v/v; 100:2 v/v; 100:3 v/v; 100:4 v/v; 100:5 v/v; methanol elution, collecting dichloromethane: the fraction eluted with methanol at 100:3v/v was purified to obtain the compound glucoptericidin a and/or 7-demethylglucoptericidin a.
The fifth purpose of the invention is to provide the application of Streptomyces sp.HBERC-58855 in the preparation of the pulveromycetin glucoside glucopteridin A and/or 7-demethylglucopteridin A.
The invention discloses the inhibitory activity of the piericidin glucoside glucoperidin A and 7-demethylglucoperidin A on three kidney cancer cells for the first time, and the piericidin glucoside can be used for preparing anti-kidney cancer drugs. Therefore, the invention provides an alternative compound for developing a new anti-renal cancer drug and has important significance for developing Chinese marine microbial drug resources.
The Streptomyces sp.HBERC-58855 is preserved in China Center for Type Culture Collection (CCTCCNO) with the preservation date of 2017, 4.20 days in Wuhan university and the preservation number of M2017186, and is disclosed in China patent-application No. CN 201710344174.3.
Description of the drawings:
FIG. 1. glucopericidin A mass spectrum;
FIG. 2. preparation of glucopericidin A1H-NMR Spectroscopy (in DMSO-d)6,700MHz)；
FIG. 3. preparation of glucopericidin A13C-NMR spectra (in DMSO-d)6,175MHz)；
FIG. 4 information relating to important COSY, HMBC and NOESY for compound 7-demethylglucoptericidin A;
FIG. 5 is a graph showing apoptosis of piericidin glucoside 7-demethylglucopericidin A on ACHN of renal cancer cells.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: preparation of the Stephania pulveromyces glucoside glucoptericidin A and 7-demethylglucoptericidin A
Solid culture of Streptomyces sp.HBERC-58855
Streptomyces sp.HBERC-58855 (preservation number is CCTCC NO: M2017186) is separated from mangrove forest bottom mud, the strain is preserved on the inclined plane of ISP-2 culture medium, and the ISP-2 culture medium comprises: 4g of yeast extract powder, 4g of glucose, 10g of malt extract powder, 30g of crude sea salt, 20g of agar powder, 1000mL of water, pH 7.2-7.4 and sterilizing for later use.
2. Scale-up fermentation of Streptomyces sp
Taking a small amount of slant Streptomyces sp.HBERC-58855 strain to perform seed fermentation culture. The culture medium is 20g of mannitol, 10g of soytone, 2.5 g of soybean oil, 0.35 g of dipotassium phosphate and 950 ml of deionized water, the pH value is adjusted to 7.0, the volume is adjusted to 1000ml, 100 ml of triangular bottles of 500 ml are filled, and the triangular bottles are sterilized for later use. The culture conditions were: at 28 ℃ and 120 rpm. After 96 hours of culture, the culture was expanded to 3L with the medium and culture conditions unchanged. Culturing for 48 hours, then performing tank fermentation, wherein the fermentation volume is 30L, the fermentation medium is 10g of glucose, 10g of soluble starch, 25 g of cottonseed meal, 3 g of yeast extract, 5 g of calcium carbonate, 2 g of sodium chloride and 950 mL of deionized water, adjusting the pH value to 7.0, fixing the volume to 1000mL, and sterilizing for later use. Culturing at 28 deg.C for 120 hr to obtain fermentation broth, extracting with ethyl acetate, and drying the extract to obtain dried extract of fermentation product of Streptomyces sp.
3. Extraction and separation
Dissolving dried extract of fermentation product of Streptomyces sp.HBERC-58855 strain with small amount of methanol, mixing with silica gel, and performing medium pressure silica gel column chromatography (200-300 mesh) with petroleum ether as eluent: dichloromethane: gradient elution with methanol system (i.e. elution sequentially with petroleum ether; petroleum ether: dichloromethane 1:1 v/v; dichloromethane: methanol 100:1 v/v; 100:2 v/v; 100:3 v/v; 100:4 v/v; 100:5 v/v; methanol) gives 9 elution positions S1-S9 (elution fractions with petroleum ether; petroleum ether: dichloromethane 1:1 v/v; dichloromethane: methanol 100:1 v/v; 100:2 v/v; 100:3 v/v; 100:4 v/v; 100:5 v/v; methanol, respectively). The S6 fraction (dichloromethane: methanol ═ 100:3v/v eluted fraction) was subjected to preparative HPLC (Hitachi-L2130 liquid chromatograph, Hitachi L-2455DAD detector, Phenomenex ODS column, 250mm × 10.0mm i.d.,5 μm, mobile phase acetonitrile: water 65:35v/v eluted at a flow rate of 1.5ml/min) to repeatedly separate and purify, yielding purified compound 1 (glucoperiridine a, Rt ═ 13.3min, 65% acetonitrile) (235mg) and compound 2 (7-demethylglucoperiridine a, Rt ═ 12.1min, 65% acetonitrile) (12.2 mg).
Example 2: structural identification of glucoptericidin A and 7-demethylglucoptericidin A
Structural identification of glucopericidin A
Mass spectrometry analysis Compound 1 (glucopericidin A) has a molecular ion peak of 600.3[ M + Na ]]+(FIG. 1), the molecular weight was 577. The NMR spectra H (FIG. 2) and C (FIG. 3) were consistent with literature reports of glucopericidin A (JAntibiost. 1987,40, 149-156), and the compound was thus identified as glucopericidin A.
The structural formula of the leptomycin compound glucopericidin A is shown as a formula (I), wherein R is CH3；
2.7 structural identification of Demethylglucopiricidin A
Compound 2 (7-demethylglucoptericidin A): a light yellow oily substance,
1.95°(c 0.20,MeOH)；IR(ATR)νmax3317,2928,1472,1456,1124,1076,1016,651,592,548cm-1；CD(0.200mg/ml,MeOH),λmax(Δ)236(1.9),200(-3.5)；1h and13c NMR data are shown in Table 1; (+)-HR-ESIMS m/z564.3185[M+H]+(calcd for C24H36NO4564.3128)。
TABLE 1.7 Demethylglucopiricidin A1H NMR and13C NMR(700MHz，CD3OD) data.
The chemical structure of the compound 7-demethylglucoptericidin A is deduced by nuclear magnetic resonance two-dimensional spectroscopy (2D NMR) analysis, and the main COSY, HMBC and NOESY related information is shown in figure 4:
the structure of the compound 2 is determined as shown in the formula (I), wherein R ═ H, and the named compound 2 is the compound 7-demethylglucoptericidin A, which is a novel compound which is not reported.
Example 3: inhibitory Activity of Glucoptericidin A and 7-demethylglucoptericidin A on renal cancer cells
Three human kidney cancers: cell lines were ordered at the Shanghai cell resource center of Chinese academy: 786-O human renal cancer cell line (Cat # TCHU186) ACHN human renal cancer cell line (Cat # TCHU 199); an OS-RC-2 human renal cancer cell line (Cat # TCTU 40). Human tubular epithelial cells HK-2 were supplied by southern university of medical college, pharmacia.
The same type of natural product, piericidin A, and the marketed drug Sorafenib (Sorafenib) for the treatment of renal cancer were used as positive controls.
The cell inhibitory activity test adopts a CCK-8 detection method. Cells in the logarithmic growth phase were collected, counted, resuspended in complete medium, adjusted to the appropriate concentration (as determined by the cell density optimization assay) and seeded into 96-well plates with 100. mu.l of cell suspension per well. Cells were cultured at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 24 hours. The test compound was diluted with the medium to the appropriate working concentration and the cells were added at 25. mu.l/well. For ACHN cells, the final concentration of test compound was started at 20 μ M, diluted in a 4-fold gradient, and 9 concentration points; for 786-O, OS-RC-2 and HK-2 cells, the concentration of test compound was started at 100. mu.M, diluted in a 4-fold gradient, and 9 concentration points. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours. The medium was aspirated off, and fresh complete medium containing 10% CCK-8 was added and incubated in an incubator at 37 ℃ for 2-4 hours. After gentle shaking, absorbance at a wavelength of 450nm was measured on a SpectraMax M5Microplate Reader, and the inhibition rate was calculated with the absorbance at 650nm as a reference.
The inhibition of cell growth by the compound was calculated as follows:
the cell growth inhibition rate [ (Ac-As)/(Ac-Ab) ]. times.100%
As absorbance OA of sample (cell + CCK-8+ test Compound)
Ac absorbance OA of negative control (cell + CCK-8+ DMSO)
Ab Absorbance OA of Positive control (Medium + CCK-8+ DMSO)
IC was performed using software Graphpad Prism 5 and using the calculation formula log (inhibitor) vs50Curve fitting and calculating IC50The value is obtained.
The proliferation inhibitory effect of the compounds on four cell lines is shown in table 2:
TABLE 2 proliferation inhibition of four cell lines by glucoptericidin A and 7-demethylglucoptericidin A (IC)50,μM)
The evaluation of the in vitro anti-renal cancer activity of two piericins glucoside shows that glucoptericidin A and 7-demethylglucoptericidin A have weaker cytotoxicity on human renal tubular epithelial cells (normal tissue cells) HK-2 and show lower toxicity; glucopericidin A has selective inhibitory activity on human renal carcinoma cell ACHN cell (half inhibition rate IC)500.21 mu M) is stronger than the positive drug sorafenib and the similar natural product Piericidin A. 7-demethylglucoptericidin A has strong broad-spectrum inhibitory activity (IC) on three renal cancer cells ACHN, OS-RC-2 and 786-O500.31-2.6 mu M), all are stronger than the inhibition activity of sorafenib on corresponding cells. The inhibitory activity on renal cancer ACHN cells is equivalent to that of piericidin A, but the inhibitory activity on renal cancer OS-RC-2 and 786-O is stronger than that of piericidin A. Therefore, the application value of glucoptericidin A and 7-demethylglucoptericidin A in the aspect of resisting renal cancer is superior to that of pirericidin A.
Example 4: effect of 7-Demethylglucopiricidin A on apoptosis of renal carcinoma cells ACHN
Taking ACHN cells in logarithmic growth phase, adjusting cell concentration to 2 × 106and/mL, inoculating into 50mL culture bottles, dividing into three batches, wherein each batch is divided into four groups, 1 group is blank control, and 7-demethylglucoptericidin A is added into 2, 3 and 4 groups respectively to make the final concentration of the mixture be 100,200 and 400 nM. After the cells are attached to the wall, the culture solution is changed and the drugs are added, wherein two batches are respectively cultured for 24h and 48h, digestion and cell collection are carried out after light microscope observation photography, and the third batch is cultured for 72 h and light microscope observation photography is carried out. The collected cells were washed with 4 ℃ pre-cooled PBS, centrifuged at 1000 r/min, 2X 5 min. After the buffer solution re-suspended the cells, 100. mu.L of cell suspension was taken and put into a flow tube, 5. mu.L of Annexin-V and 10. mu.L of PI solution were added, and after being protected from light at room temperature for 15min, the flow cytometer was used for detection.
The apoptosis pattern of ACHN in renal cancer cells under the action of different concentrations of 7-demethylglucoptericidin A is shown in FIG. 5. The results show that 7-demethylglucoptericidin A can obviously induce the apoptosis of ACHN cells under 200nM and 400nM doses.
7-demethylglucoptericidin A can remarkably induce the apoptosis of the ACHN of renal cancer cells under the concentration of 0.2 mu M. Therefore, the compounds can be used as lead compounds for developing anti-renal cancer drugs.
In conclusion, the invention provides a new candidate compound for developing a new anti-renal cancer drug, and has important significance for the development of new drugs for independent intellectual property rights in China.
Claims (6)
1. The piericidin compound shown in the formula (I),
compound 7-demethylglucoptericidin a, R ═ H.
2. The application of compound glucoptericidin A and/or 7-demethylglucoptericidin A, or its medicinal salt in preparing medicine for treating renal cancer;
the structural formulas of the compound glucoptericidin A and the compound 7-demethylglucoptericidin A are shown as follows,
compound glucopericidin A, R ═ CH3；
Compound 7-demethylglucoptericidin a, R ═ H.
3. An anti-renal cancer drug comprising an effective amount of piericidin 7-demethylglucoptericidin a according to claim 1 as an active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. A preparation method of the pulveromycetin glucoside glucoptericidin A and/or 7-demethylglucoptericidin A is characterized in that the pulveromycetin glucoside glucoptericidin A is prepared and separated from a fermentation culture of Streptomyces sp.HBERC-58855;
the structural formulas of the compound glucoptericidin A and the compound 7-demethylglucoptericidin A are shown as follows,
compound glucopericidin A, R ═ CH3；
Compound 7-demethylglucoptericidin a, R ═ H.
5. The preparation method according to claim 4, comprising the following steps: extracting fermentation product of Streptomyces sp.HBERC-58855 with ethyl acetate, concentrating the extract to obtain extract, and subjecting the extract to silica gel column chromatography with petroleum ether; petroleum ether: 1:1v/v of dichloromethane; dichloromethane; dichloromethane: methanol 100:1 v/v; 100:2 v/v; 100:3 v/v; 100:4 v/v; 100:5 v/v; methanol elution, collecting dichloromethane: the fraction eluted with methanol at 100:3v/v was purified to obtain the compound glucoptericidin a and/or 7-demethylglucoptericidin a.
6. The application of Streptomyces sp.HBERC-58855 in preparing the leptomycin glucoside glucopteridin A and/or 7-demethylglucopteridin A;
the structural formulas of the compound glucoptericidin A and the compound 7-demethylglucoptericidin A are shown as follows,
compound glucopericidin A, R ═ CH3；
Compound 7-demethylglucoptericidin a, R ═ H.
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| CN106562963A (en) * | 2016-10-31 | 2017-04-19 | 中国科学院南海海洋研究所 | Application of piericidin compound Piericidin A in preparation of anti-renal cancer drugs |
| CN107475146A (en) * | 2017-05-16 | 2017-12-15 | 中国科学院南海海洋研究所 | A kind of application of streptomycete and its metabolite piericidin class compound in anti-kidney |
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| CN106562963A (en) * | 2016-10-31 | 2017-04-19 | 中国科学院南海海洋研究所 | Application of piericidin compound Piericidin A in preparation of anti-renal cancer drugs |
| CN107475146A (en) * | 2017-05-16 | 2017-12-15 | 中国科学院南海海洋研究所 | A kind of application of streptomycete and its metabolite piericidin class compound in anti-kidney |
Non-Patent Citations (2)
| Title |
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| Glycosylated piericidins from an endophytic streptomyces with cytotoxicity and antimicrobial activity;Ning-Ning Shang，等;《The Journal of Antibiotics》;20180412;第71卷(第7期);图2 * |
| Ning-Ning Shang，等.Glycosylated piericidins from an endophytic streptomyces with cytotoxicity and antimicrobial activity.《The Journal of Antibiotics》.2018,第71卷(第7期), * |
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